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 Malariology Molecular - biology
Artemisinins resistance molecular markers in falciparum malaria in some sentinel site of Central Highland Vietnam

Huynh Hong Quang et al., 1

1Institute of Malariology, Parasitology, and Entomology Quy Nhon, MoH


Introduction: Malaria is a vector-borne disease by far the world's most important tropical parasitic disease with high mortality and morbidity, especially in tropical Africa and South East Asia. The emergence of artemisinin resistance in Vietnam as big obstacle to reduce the malaria burden and elimination. Methods: This study conducted both therapeutic efficacy in vivo test and PCR-sequencing for genotyping SNPs PF3D7_1343700 Kelch protein propeller domain in Plasmodium falciparum K13 locus. Results: these data showed that a correlation between parasite clearance and predominantly K13 mutation of C580Y with 22/29 cases (75.86%) in Gia Lai and 3/20 cases (15%) in Ninh Thuan sentinel sites in ACTs-treated patients. These mutations conferred elevated resistance to recent Cambodia, Laos, and Myanmar isolates compared with that of reference lines. Conclusion: These data provide a conclusive rationale for Central Vietnam K13-propeller sequencing to identify artemisinin-resistant falciparum parasites, but their importance in artemisinin resistance remains to be elucidated.

Key words: Plasmodium falciparum, artemisinin resistance, K13 propeller mutation


The Plasmodium falciparumparasitehas a remarkable capacity to develop resistance to antimalarial drugs by evolutionary adaptation. Artemisinin-based combination therapies (ACTs) are now recommended by the World Health Organization as first-line treatment for uncomplicated falciparum malaria. However, clinical resistance to artemisinin and its derivatives is now well established in theP. falciparum population of Cambodia, Myanmar, Laos and appears to be emerging in neighbouring regions [1],[2],[11].

The proportion of patients who are parasitemic o­n day 3, which is currently the indicator of choice for routine monitoring to identify suspected artemisinins resistance in P.falciparum. Furrthermore, PF3D7_1343700Kelch protein propeller polymorphism shows a significant association with RSA0-3?hsurvival rates [7], simultaneously matches that of slow parasite clearance which reflects the reduced susceptibility of ring stage parasites and the day 3 positivity in ACTs-treated patients [3]. As a result, K13-propeller polymorphism fulfils the definition of a molecular marker of artemisinine resistance.Consequently, there is an urgently need to discover the parasite genetic factors that cause artemisinin resistance and to identify potential markers to monitor its spread [4]. Therefore, this research of artemisinin resistance markers infalciparummalaria in Central Vietnam with following objectives:

1. To identify the prevalence of delayed parasite clearance and the frequency of single nucleotide polymorphism (SNPs) K13 propeller in malaria endemic areas;

2. To investigate the correlation between two markers (delayed parasite clearance and SNPs K13 polymorphism) and clinical artemisinin resistance in falciparum malaria.


2.1.Locations and timeframe

-The study was conducted in multi-centers in malarial hyperendemic areas at Krong Pa district (Gialai province), and Ninh Son district (Ninh Thuan province);

-From January 2015 to May 2016.

2.2.Study methods

-Study design with modified fast 7-day in vivo test protocol, Non randomised controlled study;

-Sample size: with classical statistical methods are recommended for determining sample size, o­n the basis of an expected proportion of treatment failures, desired confi­dence interval (CI 95%) and precision (10%). In the case of a medicine with an expected failure rate of 10%, a CI 95% and a precision level of 10%, a minimum of 35 patients should be enrolled.

Table 1. Calculation of sample size in vivo test

Estimated population proportion (p), confidence interval 95%


































2.3.Patients and materials

Inclusion criteria

+Age between 2 to 70 years old;

+Mono-infection with P. falciparum detected by light microscopy;

+Parasitaemia of500 - 100.000 asexual forms/l blood;

+Presence of axillary temperature ? 37.5C or history of fever (past 24h);

+Ability to swallow oral medication;

+Ability and willingness to comply with the study protocol for the duration of the study and to comply with the study visit schedule;

+Not yet take any antimalarial drugs;

+Informed consent from the patient or parents in the case of children;

Exclusion criteria

+Age under 2 years or more than 70 years old;

+Presence of general danger signs or signs of severe falciparum malaria;

+Mixed or mono-infection with another Plasmodium species;

+Presence of severe malnutrition, febrile conditions due to diseases other than malaria (acute lower respiratory tract infection, severe diarrhoea) or other known underlying chronic or severe diseases, severely vomitting, or psychological disorders;

+History of hypersensitivity reactions or contraindications to any of the medicine(s) being tested;

+A positive pregnancy test or breastfeeding women;

2.4. Antimalarial drugs to be tested in clinical trials

         Dihydroartemisinin-piperaquin phosphate (DHA-PPQ) tablet, dosage regimen as followed by latest national guidelines for malaria diagnosis and treatment (MoH, 2013).

2.5. Sampling and techniques

P. falciparum isolates were obtained from patients at calendar?s days after treatment with DHA-PPQ. Thick and thin films were stained, and the parasite densities were determined by counting the number of asexual parasites per 200 white blood cells (WBCs), assuming a WBCs count of 8.000/l. A slide was considered negative if no asexual parasites were found after counting 1,000 WBCs. Patients will be treated with DHA-PPQ and their parasite density will be measured every 12h until parasitaemia is undetectable.

Sampling capillary blood was collected by finger prick and stored in EDTA tubes;

All of standard operational procedures (SOPs) for DNA extraction, PCR, nested-PCR, quantitative parasite load by qPCR at day 0 (D0), day 3 (D3), real-time PCR amplification and standard curve using serial dilutions of DNA from cultured parasites, PCR-Sequencing for genotyping SNPs PF3D7-1343700 Kelch protein propeller domain, agarose gel electrophoresis, and genetic factors analysis conditions followed by Ariey's protocol (2014), CFX 96 and ApoE softwares [3],[7].

2.6. Ethical approval

Ethical clearances for this study from patients will be obtained from the Institutional Review Board of the Institute of Malariology, Parasitology, and Entomology (IMPE) Quy Nhon and Hue University of Medicine and Pharmacy. Work will be conducted in compliance with all relevant ethical standards and regulations governing research involving human subjects.


3.1.The trial profile and baseline characteristics of patients

Of the 56 falciparum malaria patients screened, males (64.3%) dominantly outnumbered females, and all most were in group more than 15 years old (87.1% and 88%). Seven patients (12.5%) did not fulfill the entry criteria, lost follow-up after two days treatment or lost the samples o­n D0 or D3, resulting in 49 (87.5%) patients recruited. Thirsty-three (67.3%) patients completed the 3-day course of DHA-PPQ, and 16 (32.7%) patients completed the 7-day follow-up.

Table 2. Baseline characterization of the patients, according to study site

Study site

No. cases



Median age



by PCR

on D0


parasitemia by smear

on D0



on D0

Mean hematocrit (%)

Gia Lai













Ninh Thuan















36 (73.47%)










The median malaria parasite density of asexual P. falciparum at two sentinel sites were around 12.125 (43-825.016)/mL by PCR and 26.914 (1.409-135.250)/L by microscopy. Number of cases with positive gametocyte were from 10-17.24% in Gia Lai, and Ninh Thuan, respectively.

Table 3. Baseline clinical patient's profile at the D0

Studied patient's profile

At the point start of study D0

Gia Lai

(n = 29 )

Ninh Thuan

(n = 20)


(N = 49)

Temperature & body weight

Mean temperature in 0C

Mean weight in kg

Fever day number before test


37.78 1.2

36.5 18.2

2.6 1.1


38.16 1.0

39.5 15

2.2 1.2


38.19 1.0

38.5 12.0

2.4 1.2

Fever or history of fever

Body temperature ? 37.50C

History of fever(past 48 hours)


23 (79.3%)

3 (10.34%)





37 (75.5%)

6 (12.24%)

Only 12.24% of patients, the o­nset of fever occurred within the previous 72 h, and 75.5% had measurable fever at the time of recruitment.

3.2.The parasite clearance rate

Table 4. The efficacy of DHA-PPQ in parasite clearance



Total (N = 49)

Gia Lai (n = 29)

Ninh Thuan (n = 20)







































The parasite clearance rate was assessed in 49 patients. Number of non-delayed parasite clearance_DPC) rate in general were obviously different by qPCR and by microscopy, 32.7% and 79.6%, respectively or DPC of 67.3%by qPCR and 20.4% by microscopy.

 Fig 1. Distribution of malaria patients according to their age

           The highlights of the DPC, or proportion of positive asexual P. falciparum atD3 rate in Gia Lai was extremely high with 86.2% and 40% in Ninh Thuan. With in total 49 patients, 16 (32.7%) patients completed the 28-day follow-up, there were 9 (56.3%) cases were positive at Dq28 by qPCR with low parasitemia (from 1- 43 parasites/l).

Analysis of all 33 cases with parasite positive o­n D3 (t72), 7 (21.2%) patients had the residual parasitemia after 72 h was more than 1% (severe DPC), and all the other patients with DPC, residual parasitemia was less than 1 % (Mild DPC). Age distributions followed No DPC, Mild DPC and Servere DPC have no significantly difference (Fig. 1).

Fig2. In parasite clearance 72 hours after teatment (t72), samples have been grouped according to the residual parasitemia at t72:
Samples without measurable parasitemia at time 72
h (No DPC), samples with residual parasitemia <1% (Mild DPC), and samples with
residual parasitemia >1% (Severe DPC).

3.2.1. Delayed parasite clearance in Gia Lai

Totally 29 cases in Gia Lai, the highlights of the DPC, or proportion of positive asexual P. falciparum at D3 rate in Gia Lai was extremely high with 86.2% by qPCR, even though very high rate 31% by microscopy. Within Fig 2, there were 6 cases which were severe DPC. They also located in Gia Lai (Fig 2- Severe DPC in Gia Lai). Another 19 cases were in Mild DPC, just o­nly 4 cases were No DPC.

 Fig 3. Parasite clearence 72 hours after teatment (t72) with DHA-PPQ in Gia Lai

3.2.2.Delayed parasite clearance in Ninh Thuan

 Fig 4. Parasite clearance 72 hours after teatment (t72)withDHA-PPQ in Ninh Thuan

Almost No DPC cases within our research located in Ninh Thuan was confirmed in this site. In addition to, there were the others of 6 cases were in mild DPC.

3.3.Nonsynonymous SNPs Kelch 13 polymorphisms observed in P. falciparum isolates

3.3.2.Result of Nested PCP of K13 gene in agarose gel electrophoresis


 Fig 5.PCR products for Secondary N1 PCRfor K13 gene

S1: tested samples, Neg: PCR negative controls

M: 1000bp marker; Expected size of PCR product: 849 bp

3.3.3.Nonsynonymous SNPs Kelch-13 polymorphisms observed in the P. falciparum isolates

Table 5. Polymorphisms observed in the K13-propeller P. falciparum isolates

Study site

No.of patients /

Total no. (%)

Codon position

Amino Acid reference

Nucleotide reference

Amino Acid Mutation

Nucleotide Mutation

Gia Lai

(n= 29)

22 (75.86%)






Ninh Thuan


3 (15%)






Total (n= 49)

25 (51 %)






           A total of 49 collected samples were examined for the SNPs of the K13 propeller domain. Just o­nly C580Y was obtained. The overall prevalence of the mutant allele was 51% (25/49). However, the mutant allele obtained were in Gia Lai with 75.86% (22/29), meanwhile, the prevalence of C580Y in Ninh Thuan was 15% (3/20).

In comparison with classification of K13 polymorphism (Followed by WHO, 2015) K13 mutant alleles C580Y observed in two province, Gia Lai and Ninh Thuan was reported indicate emergingartemisinin resistance. It is o­ne of confirmed K13 propellermutations(i.e. those confirmed by in vivo and in vitro data).

3.4.The correlation between the K13 polymorphisms and delayed parasite clearance

3.4.1.Correlation between the frequency ofK13-propeller alleles and the prevalence of D3(+)

Table 6. Comparison with classification of K13 polymorphism with WHO reference (2015)

                   Table 7. The frequency of K13 mutants correlated to the prevalence of DPC


The frequency / the prevalence



(n = 49)

Gia Lai

(n = 29)

Ninh Thuan

(n = 20)








Wild-type K13-propeller alleles








Mutant K13-propeller alleles








DPC with mutant K13-propeller alleles








DPC with wild-type K13-propeller alleles








No DPC with mutant K13 alleles








No DPC with wild-type K13 alleles







All of 49 patients, 25 (51.02%) cases had mutant K13 propeller alleles, mostly 44.9% (22/49) were positive of parasite o­n day 3 after treatment, just o­nly 3 cases had K13 mutant (6.12%) were negative with DPC. And mostly cases of DPC with K13 mutant occurred in Gia Lai in 90.9 % (20/22). Very few patients of positive DPC with K13 mutant were obtained in Ninh Thuan in 9.1% (2/22).

 Fig 6. The number of cases positive with delayed parasite clearance and K13 mutant alleles

            The presence of C580Y mutant was obtained mostly in the mild DPC group, followed by severe DPC group. In general, the number cases of mild DPC and severe DPC correlated with the frequency of K13 propeller C580Y. Almost patients have no delayed parasite clearance were obtained with wild type K13 mutant alleles. The sensitivity and specificity of the SNP 580Y at day 0 to identify delayed clearance (PCT, ? 72h) were therefore estimated at 71.88% (22/32) and 82.35% (14/17), respectively; the positive predictive value of the mutation was 88% (22/25), while the negative predictive value of the wild-type allele was 58.33% (14/24). The cases positive with K13 mutation and also DPC mostly occurred in Gia Lai.

3.4.2. Correlation between the frequency ofK13-propeller alleles and the proportion D3 (+)

The mutant allele obtained were in Gia Lai with extremely high prevalence 75.86% (22/29), compared to the frequency of C580Y in Ninh Thuan was 15% (3/20). 22 cases were positive of K13 mutantation and DPC, mostly occurred in Gia Lai,just2 cases were obtained in Ninh Thuan. Within a large number of patients had the C580Y allele (25/49), all of 6 patients of severe DPC group had C580Y mutation were obtained in Gia Lai. No patient of severe DPC with C580Y was obtained in Ninh Thuan. Just o­nly 2 patients had C580Y allele were found in mild DPC group and the other o­ne in No DPC group. All most No DPC patients with K13 wild type allele were found in Ninh Thuan, 12 in 14 totally.

3.4.3.Correlation between the frequency ofK13-propeller alleles and several cases were positive at D28 after ACT treatment

 Fig 7. The number of cases positive with delayed parasite clearance and K13 mutant alleles

Within totally 49 patients, 16 (32.7%) patients completed the 28-day follow-up, there were 9 (56.3%) cases were positive at D28 by qPCR with low parasitemia (from 1-43 parasites/l). Just o­nly 2 cases in Gia Lai were confirmed to carry K13 mutant allele C580Y.


4.1.Baseline characterization of the patients and efficacy of DHA-PPQ in parasite clearance

All of 49 patients with the median malaria parasite density of asexual P. falciparum at two sites Gia Lai and Ninh Thuan were 14.150 and 9.038 parasites/ respectively. The low median parasitemia in two provinces are not an effect to be considered as the factor contributing to delay in parasite clearance [5],[6]. Compared to microscopy, the prevalence of parasite densities by qPCR detected increasingly more infections over time, and the difference became significant at day 3, when the prevalence by PCR was 3.3 times higher than that by microscopy (67.3% vs. 20.4%; p < 0.01). Notably, the proportion of positive parasitemia at D3 in Gia Lai province was extremely high, 86.2% by qPCR and 31 % by microscopy; in Ninh Thuan was 40% by qPCR and 5% by microscopy, which is currently the indicator of choice for routine monitoring to identify suspected artemisinin resistance in P. falciparum.
         Using qPCR with high sensitivity and specificity, the number of positive parasitemia o­n D3 observed by qPCR much higher in comparing with microscopic evaluation. However, within the large range of parasitemia o­n D3 observed by qPCR, we divided all 33 delayed parasite clearance cases into two group mild DPC (
with residual parasitemia <1%) and severe DPC (residual parasitemia >1%). In the mild DPC group, the parasitemia was low, from 1 to less 10 parasites/l. No evidence showed that the very low parasitemia detected by qPCR probably was death parasite or not. Almost mild DPC cases focussed in Gia Lai and in contrast, No DPC cases focussed in Ninh Thuan mainly, and it is necessary to have further study about it. 
           About the DHA-PPQ efficacy in Gia Lai, specially, there were just o­nly 6 cases in severe DPC group which located in Gia Lai, where the median parasitemia and the prevalence of D3 positive after ACTs treatment were confirmed to be higher than in Ninh Thuan. High parasitemia o­n D3 after using DHA-PPQ in severe DPC group is unlikely that was the immunity profile cause of the observed delayed parasite clearance. It is necessary to complete futher study about the immunity profile of the community and the individual, also the pharmacokinetics and pharmacodynamics of the antimalarial drug to understand this situation. High prevalence of positive parasitemia o­n D3 was also similar to the other sites in the Gia Lai, Dak Nong, Quang Nam [8], Khanh Hoa, Binh Phuoc [5],[6]. The the proportion of positive parasitemia at D3 in Binh Phuoc was from 15% up to 22%; 30%; 36%, and 36.8% year by year from 2010 to 2015, in Quang Nam of 29.2%, Kon Tum of 14%, Khanh Hoa of 17.4%, Dak Nong was from 29% up to 26.7% from 2012 to 2014, and Gia Lai was from 11% up to 23%; 26.4% and 38.5% from 2010 to 2014. Not o­nly Vietnam but also the other countries in South East Asia, the the proportion of positive parasitemia at D3 in Cambodia increased continuously year by year 26% up to 33%; 45% and 54% from 2008 to 2012, in Myanmar from 14% up to 19%; 23% from 2012 to 2013 or Thailand was from 9% up to 14%; 17%; 25% and 48% from 2009 to 2014.

About the DHA-PPQ efficacy, with 16 cases followed up to D28, the adequate clinical and parasitological response (100% in Ninh Thu?n and 97.4% in Gia Lai), negative parasitaemia o­n D28 was 56.3% (9/16) confirmed by qPCR, divided into two province equally. And all of cases were positive at D28 had the proportion of positive asexual P. falciparum at D3 by qPCR. This result is different to previous researchs of Vietnam [5],[6]. It probably caused by using different sensitivity methods to detect parasitemia. It is necessary to to apply with the other samples to assess the DHA-PPQ efficacy.

Moreover, age distributions followed No DPC, mild DPC and servere DPC have no significantly difference (Fig 12). As expected from previous work, young children had slower parasite clearance rates compared to older patients. However, this was observed o­nly in artemisinin-sensitive parasite populations, with most data coming from Africa. Resistant parasite populations, present o­nly in Southeast Asia, did not demonstrate an age effect. The lack of an age effect o­n DPC could be due to o­ne or more of the following factors: lower background immunity in those patients from low transmission settings, different age distributions studied with 87.5% of patients aged older than 15 years.

4.2.Frequency of non synonymous Kelch 13 polymorphisms observed in P. falciparum isolates

In this study, the overall prevalence of the mutant allele was 51% (25/49). And the C580Y mutant allele was o­nly o­ne SNPs K13 propeller found in all cases positive with K13 mutation. Notably, the C580Y substitutions that was confirmed to correlate to in vitro resistance or delayed parasite clearance - a confirmed mutation alleles inclassification of K13 polymorphism as WHO reference in Southeast Asia.About the correlation between the K13 polymorphisms and delayed parasite clearance, the presence of C580Y mutant was obtained mostly in the mild DPC group, followed by severe DPC group. In addition, almost no DPC cases had wild-type K13 mutant allele. In general, the number cases of mild DPC and severe DPC correlated with the frequency of K13 propeller C580Y.

However, the mutant allele obtained were in Gia Lai with extremely high prevalence compared to the prevalence of C580Y in Ninh Thuan (75.86% vs. 15%). The cases positive with K13 mutation and also DPC mostly occurred in Gia Lai. Furthermore, C580Y K13 alleles mainly were obtained in mild DPC group. This data gave the correlation between the delayed parasite clearance and the K13 mutation in this sites (p = 0.002). o­n the contrary, in Ninh Thuan, no DPC showed a relevent data to K13 wild-type. Considering that the high prevalence of delayed parasite clearance and K13 mutant alleles, Gia lai fulfills the WHO definition of confirmed artemisinin resistance and Ninh Thuan as suspected artemisinin resistance.

4.4. The correlation between the K13 mutations, DPC, and artermisinin resistant P. falciparum

The frequency distribution of mutant alleles over two provinces matches that of day 3 positivity in ACTs-treated patients. The mutant parasites cluster in Gia Lai provinces where the delayed parasite clearance is well established and are less prevalent where DPC is less common in Ninh Thuan. The study was designed as a 28-day follow-up study to assess the efficacy of DHA-PPQ in treating falciparum malaria. Despite the fact that no recrudescent case was obtained during the researching time, there were 9 cases were positive at D28 by qPCR with low parasitemia. The hypothesis of death parasite could be detected until D28. It also means that the parasite could be still alive until after day 20 at least. Within 9 cases were positive of asexual parasite o­n D28, two of them also carried C580Y mutant alleles. It seems to be a strong evidence of the correlation between K13 mutation and delayed parasite clearance [9]. Nevertheless, no evidence of rescrudescence was showed. It leads to the other hypothesis that the patiens with positive of parasite o­n D28 could become a asymptomatic carrier [10].

In study, the frequency of mutant alleles correlates strongly with the prevalence of D3 positivity after ACT treatment; however, both K13 mutant alleles and DPC were not associated with artemisinin resistance. In fact, totalof186K13alleles,including108non-synonymousmutations havebeenreporteduntil now. However, notallnon-synonymouspropeller-regionK13 mutantsreportedindicateemergingartemisinin resistance. Besides, the emergence of SNPs K13 propeller and the spread of artemisinin seem to be independent. Notebly, the widespread 580Y mutation seems to have emerged twice. Given that frequency distribution suggests a Cambodian origin, where the mutations are most prevalent, with subsequent spread to Vietnam and maybe to Africa [9]. Howerver, our study site in Krong Pa, Gia Lai does not share the border with Cambodia, therefore, C580Y allele maybe o­ne of indigenous mutation. It created ?the gap, the blacklash? o­n Tier 1 map o­n Central highland of Vietnam. Although few P. falciparum isolates were recruited in Ninh Thuan, it shows the high prevalence of DPC with low frequency of K13 mutations, it is indispensable to continue further study to assess the DHA-PPq efficacy for P. falciparum infection in this area and interprete the role of K13 mutant alleles in this area.


Up-to-date information o­n whether artemisinin resistance has already disseminated or independently emerged is a critical issue. If resistance were limited to a small, well-defined area, then elimination of drug-resistant malaria from these regions would be possible. More works are needed to delineate the normal function of K13 and the effect of various mutations besides studies are therefore required to identify additional genetic determinants of artemisinin resistance.

Conflict of interest

The authors have no other conflicts of interest.


This study is partly supported by the donations of World Health Organization (WHO), Sassari University, Institute of Malariology, Parasitology, and Entomology (IMPE) Quy Nhon, Vietnam and Hue University of Medicine and Pharmacy.


1.Boull M, Witkowski B, Valentine Duru, Kanlaya Sriprawat, Nair SK, McDew-White M, Anderson TJC, Phyo AP, Menard D, Nosten F (2016). Artemisinin-resistant Plasmodium falciparum K13 mutant alleles, Thailand-Myanmar Border. Emerging Infectious Diseases, 22(8):1503-1055.

2.Amaratunga C, Sreng S, Suon S, Phelps ES, Stepniewska K, Lim P, et al (2012). Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study. The Lancet Infectious Diseases, 12(11):851-858.

3.Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois AC, et al (2014). A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature, 505(7481):50-55.

4.Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, et al (2014). Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med, 371(5):411-423.

5.Bui QP, Ta TT, Huynh HQ, Nguyen MH (2013). Efficacy of artesunate monotherapy and Dihydroartemisinine plus piperaquine therapy in the treatment for uncomplicated falciparum malaria in Vietnam, 2012. Journal of medicine of Ho Chi Minh, Vietnam, 17(Supplement of No 1):31-35.

6.Hien TT, Thuy-Nhien NT, Phu NH, Boni MF, Thanh NV, Tagbor H, et al (2012). In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam. Malaria journal, 11(1):355.

7.Takala-Harrison S, Clark TG, Jacob CG, Cummings MP, Miotto O, Dondorp AM, Fukuda MM, et al (2013). Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia. Proceedings of the National Academy of Sciences of the United States of America, 110(1):240-245.

8.Thriemer K, Hong N, Rosanas-Urgell A, Phuc B, M H, Pockele E, Guetens P VN, Duong TT, Amambua-Ngwa A, D'Alessandro U, Erhart A. (2014). Delayed Parasite Clearance after Treatment with Dihydroartemisinin-Piperaquine in Plasmodium falciparum Malaria Patients in Central Vietnam. Antimicrob. Agents Chemother, 58(12):7049-7055.

9.Muhindo MK KA, Jagannathan P, et al (2014). Early parasite clearance following artemisinin-based combination therapy among Ugandan children with uncomplicated Plasmodium falciparum malaria. Malar J., 13(1):32.

10.Takala-Harrison S, Jacob CG, Arze C, Cummings MP, Plowe CV, et al (2015). Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia. J Infect Dis, 211(5):670-679.

11.WHO (2015). Status report o­n artemisinin and ACT resistance September 2015.1-8.

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